Differential block of peripheral nerve fibers conveying pain is the long term goal of this research. It presupposes knowledge of the differential action of local anesthetics on different types of nerve fibers and an understanding of how this bears on the differential blocks that occur in daily practice. Single fiber single shock findings having undermined current explanations derived from studies of compound action potentials, it is now necessary to determine the differential effect of trains of shocks. They imitate natural nerve activity and intensify the conduction block produced by dilute local anesthetic in frog nerve. The determinants of this "use-dependent" effect so far have hardly been studied in mammalian nerve, which differs from amphibian in some important respects, nor individual fibers during conduction, so that its role in differential block in man remains essentially unknon. The project undertakes a systematic investigation of use-dependent block in single myelinated nerve fibers of a wide range of conduction velocities, and single unmyelinated fibers, in excised vagus, recurrent laryngeal, and cervical sympathetic nerves form rabbit. It will test different frequencies of nerve impulses, different lengths of nerve fiber, and several subblocking concentrations of three leading local anesthetics, bupivacaine, lidocaine and tetracaine, as well as etidocaine, of suitably different lipid solubility and potency. The results will enable evaluation of use-dependent block as a potential contributor to the differential sympathetic paralysis that often precipitates fall of blood pressure in subarachnoid regional anesthesia. Understanding of the action of local anesthetics in the treatment of cardiac arrhythmias may also benefit. Use-dependent effects should also be evaluated in the differential block of epidural regional anesthesia, where motor power is often usefully preserved in the analgesic area. This evaluation will require, in addition, measurements on the length and thickness and arachnoid granulation content of the dural sleeve of spinal nerve roots and adjoining perineurium, which are a probable main site of action of epidural block. Such data are not presently available from man, but will be obtained in this project by photographic and histological study of specimens removed from the lumbar and lower thoracic regions at autopsy, after epidural injection of dye to reveal the limits of spread.